The present invention relates to new heterocyclylmethyl-substituted pyrazole derivatives, processes for their preparation and their use as medicaments, in particular as medicaments for treatment of cardiovascular diseases.
It is already known that 1-benzyl-3-(substituted heteroaryl)-fused pyrazole derivatives inhibit stimulated platelet aggregation in vitro (cf. EP 667 345 A1). I
The present invention relates to new heterocyclylmethyl-substituted pyrazole derivatives, in the embodiment designated I (roman one), of the general formula (I-I) 
in which
R1xe2x80x2 represents a 5-membered aromatic heterocyclic ring having one heteroatom, from the series consisting of S, N and/or O, or represents phenyl, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, mercaptyl, hydroxyl, straight-chain or branched acyl, is alkylthio, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula xe2x80x94OR4, wherein
R4 denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula xe2x80x94SiR5R6R7, wherein
R5, R6 and R7 are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms,
and/or are substituted by a radical of the formula 
xe2x80x83wherein
b1 and b1xe2x80x2 are identical or different and denote the number 0, 1, 2 or 3,
a1 denotes the number 1, 2 or 3,
R8 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
c1 denotes the number 1 or 2 and
R9 and R10 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or
denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or
denote cycloalkyl having 3 to 7 carbon atoms, or R9 and R10, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical xe2x80x94NR11,
xe2x80x83wherein
R11 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula 
or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen,
R2 and R3, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of S, N and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, wherein the alkyl in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,
and/or are optionally substituted by a radical of the formula xe2x80x94S(O)c1xe2x80x2NR9xe2x80x2R10xe2x80x2, wherein c1xe2x80x2, R9xe2x80x2and R10xe2x80x2 have the abovementioned meaning of c1, R9 and R10 and are identical to or different from these,
A1 represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O, which is optionally substituted up to 3 times in an identical or different manner by mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,
and/or is substituted by a group of the formula xe2x80x94(CO)d1xe2x80x94NR12R13, wherein
d1 denotes the number 0 or 1,
R12 and R13 are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms,
and their isomeric forms, salts and their N-oxides.
The compounds of the general formula (I-I) according to the invention can also be present in the form of their salts. Salts with organic or inorganic bases or acids may be mentioned in general here.
In the context of embodiment I of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the heterocyclylmethyl-substituted pyrazole derivatives can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
The compounds according to the invention can exist in stereoisomeric forms which either behave as mirror images (enantiomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or diastereomers or their particular mixtures. The racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.
Heterocyclic ring in the context of embodiment I of the invention, and depending on the abovementioned substituents, in general represents a 5- to 6-membered heterocyclic ring which can contain 1 heteroatom in the 5-membered ring in the case of R1 and up to 3 heteroatoms from the series consisting of S, N and/or O in the case of A. Examples which may be mentioned are: pyridazinyl, pyridyl, pyrimidyl, thienyl, furyl, morpholinyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrahydropyranyl or tetrahydrofuranyl. Furyl, pyridyl, thienyl, pyrrolyl, pyrimidyl, pyridazinyl, morpholinyl, tetrahydropyranyl or tetrahydrofuranyl are preferred.
Preferred compounds of the general formula (I-I) according to the invention are those in which
R1 represents furyl, pyrrolyl, thienyl or phenyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms or by a radical of the formula xe2x80x94OR4, wherein
R4 denotes straight-chain or branched acyl having up to 4 carbon atoms,
and/or are substituted by a radical of the formula 
xe2x80x83wherein
a1 denotes the number 1, 2 or 3,
R8 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R2 and R3, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
A1 represents tetrahydropyranyl, thienyl, furyl, tetrahydrofuranyl, pyrazinyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, and/or are substituted by a group of the formula -(CO)d1, xe2x80x94NR12R13, wherein
d1 denotes the number 0 or 1,
R12 and R13 are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms,
and their isomeric forms and salts and their N-oxides.
Particularly preferred compounds of the general formula (I-I) according to the invention are those in which
R1 represents furyl, pyrryl, thienyl or phenyl, which are optionally substituted up to twice in an identical or different manner by formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms,
and/or are substituted by a radical of the formula 
xe2x80x83wherein
a1 denotes the number 1 or 2,
R8 denotes hydrogen or methyl,
R2 and R3, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,
A1 represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, furyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,
and/or are substituted by a group of the formula xe2x80x94(CO)d1xe2x80x94NR12R13, wherein
d1 denotes the number 0 or 1,
R12 and R13 are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms,
and their isomeric forms and salts and their N-oxides.
Especially preferred compounds of the general formula (I-I) according to the invention are those in which
R1 represents furyl, which is optionally substituted by formyl or by radical of the formula 
R2 and R3, including the double bond, form a phenyl ring which is substituted by phenyl, fluorine or nitro,
A1 represents furyl, pyridyl, pyrimidyl, pyridazinyl, thienyl, tetrahydrofuranyl or tetrahydropyranyl, which are optionally substituted by chlorine, bromine, methoxy, methoxycarbonyl or carboxyl,
and their salts, isomeric forms and N-oxides.
The invention furthermore relates to processes for the preparation of the compounds of the general formula (I-I) according to the invention, characterized in that
[A1] compounds of the general formula (I-II) 
xe2x80x83in which
R1, R2 and R3 have the abovementioned meaning,
are reacted with compounds of the general formula (I-III)
D1xe2x80x94CH2xe2x80x94A1xe2x80x83xe2x80x83(I-In)
xe2x80x83in which
A1 has the abovementioned meaning and
D1 represents triflate or halogen, preferably bromine,
in inert solvents, if appropriate in the presence of a base, or
[B1] compounds of the general formula (I-IV) 
xe2x80x83in which
A1, R2 and R3 have the abovementioned meaning and
L1 represents a radical of the formula xe2x80x94SnR14R15R16, ZnR17, iodine or triflate, wherein
R14, R15 and R16 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and
R17 denotes halogen,
are reacted with compounds of the general formula (I-V)
R1xe2x80x94T1xe2x80x83xe2x80x83(I-V)
xe2x80x83in which
R1 has the abovementioned meaning and
in the case where L1=SnR14R15R16 or ZnR17,
T1 represents triflate or represents halogen, preferably bromine, and
in the case where L1=iodine or triflate,
T1 represents a radical of the formula SnR14xe2x80x2R15xe2x80x2R16xe2x80x2, ZnR17xe2x80x2 or BR18R19, wherein
R14xe2x80x2, R15xe2x80x2, R16xe2x80x2 and R17xe2x80x2have the abovementioned meaning of R14, R15, R16 and R17 and are identical to or different from these,
R18 and R19 are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,
in a palladium-catalysed reaction in inert solvents,
and, in the case of the radicals xe2x80x94S(O)c1NR9R10 and xe2x80x94S(O)c1xe2x80x2NR9xe2x80x2R10xe2x80x2, starting from the unsubstituted compounds of the general formula (I-I), these are first reacted with thionyl chloride, and finally the amine component is employed,
and, if appropriate, the substituents listed under R1, R2, R3 and/or A1 are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.
The processes according to the invention can be illustrated by way of example by the following equations. 
Suitable solvents here for the individual steps of process [A1] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.
Bases which can be employed for the process according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trialkyl- (C1-C6)amines), such as triethylamine, or heterocyclic compounds, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine and sodium hydride are preferred.
The base is employed in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (I-II).
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.
Suitable solvents here for process [B1] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.
Suitable palladium compounds in the context of the present invention are in general PdCl2(P(C6H5)3)2, palladium bis-dibenzylideneacetone (Pd(dba)2), [1,1xe2x80x2-bis-(diphenyl-phosphino)ferrocene]-palladium(II) chloride (Pd(dppf)Cl2) or Pd(P(C6H5)3)4. Pd(P(C6H5)3)4 is preferred.
The compounds of the general formulae (I-III) and (I-V) are known per se or can be prepared by customary methods.
The compounds of the general formula (I-II) are known in some cases or are new, and can then be prepared by a process in which compounds of the general formula (I-VI) 
in which
R2 and R3 have the abovementioned meaning and
L1xe2x80x2 has the abovementioned meaning of L1 and is identical to or different from this,
are reacted with compounds of the general formula (I-V) analogously to the abovementioned process [B1].
The compounds of the general formula (I-IV) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by a process in which the compounds of the general formula (I-IVa) 
in which
R2, R3 and A1 have the abovementioned meaning,
and
L1xe2x80x2 represents triflate or halogen, preferably iodine,
are reacted with compounds of the general formula (I-VII)
(SnR14R15R16)2xe2x80x83xe2x80x83(I-VII)
in which
R14, R15 and R16 have the abovementioned meaning,
under palladium catalysis, as described above.
The compounds of the general formulae (I-IVa) and (I-VII) are known per se or can be prepared by customary methods.
The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydrido-boranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.
The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.
The reduction in general proceeds in a temperature range from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C., in the case of DIBAH, 0xc2x0 C., room temperature in the case of NaBH4, particularly preferably at xe2x88x9278xc2x0 C., in each case depending on the choice of reducing agent and solvents.
The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.
The protective group is in general split off in one of the abovementioned alcohols and/or THF or acetone, preferably methanol/THF, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0xc2x0 C. to 70xc2x0 C., preferably at room temperature under normal pressure.
In the case where the radicals of the formulae xe2x80x94S(O)c1NR9R10 and xe2x80x94S(O)c1xe2x80x2NR9xe2x80x2R10xe2x80x2 are present, the corresponding unsubstituted compounds are first reacted with thionyl chloride. The reaction with the amines in one of the abovementioned ethers, preferably dioxane, is carried out in a second step. In the case where c1=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in a temperature range from 0xc2x0 C. to 70xc2x0 C. under normal pressure. The invention moreover relates to the combination of the compounds of the general formula (I-I) according to the invention with organic nitrates and NO donors.
Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the liberation of NO or NO species. Sodium nitroprusside (SNP), nitroglycerol, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-I and similar substances are preferred.
The invention also relates to the combination with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular, inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pages 150-155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect increased by these inhibitors.
The compounds of the general formula (I-I) according to the invention show an unforeseeable, valuable pharmacological action spectrum.
The compounds of the general formula (I-I) according to the invention lead to a vessel relaxation, to an inhibition of platelet aggregation and to a lowering of blood pressure, as well as to an increase in coronary blood flow. These actions are mediated via direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. Furthermore, the compounds according to the invention intensify the action of substances which increase the cGMP level, such as, for example, EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives. They can therefore be employed in medicaments for treatment of cardiovascular diseases, such as, for example, for treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris and peripheral and cardiac vascular diseases and of arrhythmias, for treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transitory and ischaemic attacks and peripheral circulatory disturbances, for preventing restenoses, such as after thrombolysis treatment, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass, and for treatment of arteriosclerosis and diseases of the urogenital system, such as, for example, prostate hypertrophy, erectile dysfunction and incontinence.
The following investigations were carried out to determine the cardiovascular actions: the influence on guanylate cyclase-dependent cGMP formation with and without an NO donor was tested in investigations in vitro on cells of vascular origin. The anti-aggregatory properties were demonstrated on human platelets stimulated with collagen. The vessel-relaxing action was determined on rabbit aortic rings precontracted with phenylephrine. The antihypertensive action was investigated on anaesthetized rats.
Stimulation of Soluble Guanylate Cyclase in Primary Endothelial Cells
Primary endothelial cells were isolated from pig aortas by treatment with collagenase solution. The cells were then cultured in a culture medium until confluence was reached. For the investigations, the cells were subjected to passaging, sown in cell culture plates and subcultured until confluence was reached. To stimulate the endothelial guanylate cyclase, the culture medium was suctioned off and the cells were washed once with Ringer""s solution and incubated in stimulation buffer with or without an NO donor (sodium nitroprusside, SNP, 1 xcexcM). Thereafter, the test substances (final concentration 1 xcexcM) were pipetted onto the cells. At the end of the 10-minute incubation period, the buffered solution was suctioned off and the cells were lysed at xe2x88x9220xc2x0 C. for 16 hours. The intracellular cGMP was then determined radioimmunologically.
Vessel-relaxing Action in vitro
Rings 1.5 mm wide of an aorta isolated from a rabbit are introduced individually, under pretension, in 5 ml organ baths with Krebs-Henseleit solution warmed to 37xc2x0 C. and gassed with carbogen. The contraction force is amplified and digitalized and recorded in parallel on a line recorder. To generate a contraction, phenylephrine is added cumulatively to the bath in an increasing concentration.
After several control cycles, the substance to be investigated is investigated in each further pass in each case in an increasing dosage, and a comparison is made with the level of the contraction achieved in the last preliminary pass. The concentration necessary to reduce the level of the control value by 50% (IC50) is calculated from this. The standard application volume is 5 xcexcl.
Blood Pressure Measurements on Anaesthetized Rats
Male Wistar rats with a body weight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is inserted into the femoral artery for blood pressure measurement. The substances to be tested are administered orally by means of a stomach tube in various doses as a suspension in tylose solution.
Inhibition of Platelet Aggregation in vitro
To determine the platelet aggregation-inhibiting action, blood from healthy subjects of both sexes was used. One part of 3.8% strength aqueous sodium citrate solution was admixed to 9 parts of blood as an anticoagulant. Platelet-richer citrate plasma (PRP) is obtained from this blood by means of centrifugation.
For the investigations, 445 xcexcl of PRP and 5 xcexcl of the active compound solution were preincubated in a water-bath at 37xc2x0 C. The platelet aggregation was then determined in an aggregometer at 37xc2x0 C. For this, 50 xcexcl of collagen, an aggregation-inducing agent, were added to the preincubated sample and the change in optical density was recorded. For the quantitative evaluation, the maximum aggregation response was determined and the percentage inhibition compared with the control was calculated therefrom.
The compounds described in embodiment I of the present invention are also active compounds for combating diseases in the central nervous system which are characterized by impairments of the NO/cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory performance and for treatment of Alzheimer""s disease. They are also suitable for treatment of diseases of the central nervous system such as states of anxiety, stress and depression, sexual dysfunctions of central nervous origin and sleep disturbances, and for regulating pathological disturbances in the intake of food and addictive substances.
These active compounds are furthermore also suitable for regulation of cerebral circulation and are therefore effective agents for combating migraine.
They are also suitable for prophylaxis and combating the consequences of cerebral infarction events (apoplexia cerebri), such as apoplexy, cerebral ischaemias and cranio-cerebral trauma. The compounds according to the invention can also be employed for combating states of pain.
The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.
If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.
The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.
In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.
II
The present invention relates to new 1-heterocyclyl-methyl-substituted pyrazoles, in the embodiment designated II (roman two), of the general formula (II-I), 
in which
R20 represents a 6-membered aromatic heterocyclic ring having up to 3 nitrogen atoms, which is optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl and/or by a group of the formula
xe2x80x94NR23R24
wherein
R23 and R24 are identical or different and denote hydrogen or straight-chain or branched acyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 5 carbon atoms, or
R23 and R24, together with the nitrogen atom, form a 3- to 7-membered saturated or partly unsaturated heterocyclic ring, which can optionally additionally contain an oxygen or sulphur atom or a radical of the formula xe2x80x94NR25,
xe2x80x83wherein
R25 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and/or is substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, halogen, carboxyl, straight-chain branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula xe2x80x94OR26,
xe2x80x83wherein
R26 denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula xe2x80x94SiR27R28R29, wherein
R27, R28 and R29 are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms,
and/or is optionally substituted by a radical of the formula 
xe2x80x83wherein
b2 and b2xe2x80x2 are identical or different and denote the number 0, 1, 2 or 3,
a2 denotes the number 1, 2 or 3,
R30 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
c2 denotes the number 1 or 2 and
R31 and R32 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or
denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or
denote cycloalkyl having 3 to 7 carbon atoms, or
R31 and R32, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further
oxygen atom or a radical xe2x80x94NR33, wherein
R33 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula 
or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen,
R21 and R22, including the double bond, form a 5-membered aromatic heterocyclic ring having a heteroatom from the series consisting of S, N and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, mercaptyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkylthio, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, or are optionally substituted by a group of the formula xe2x80x94S(O)c2xe2x80x2NR31xe2x80x2R32xe2x80x2 wherein c2xe2x80x2, R31xe2x80x2 and R32xe2x80x2 have the abovementioned meaning of c2, R31 and R32 and are identical to or different from these,
A2 represents phenyl or a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O, which are optionally substituted up to 3 times in an identical or different manner by mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula xe2x80x94(CO)d2xe2x80x94NR34R35, wherein
d2 denotes the number 0 or 1,
R34 and R35 are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms,
their isomeric forms and salts and their N-oxides.
In the context of embodiment II of the present invention, physiologically acceptable salts with organic or inorganic bases or acids are preferred. Physiologically acceptable salts of the 1-heterocyclyl-methyl-substituted pyrazoles can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
The compounds according to the invention according to embodiment II can exist in stereoisomeric forms which either behave as mirror images (enantiomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or diastereomers or their particular mixtures. The racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner. Heterocyclic ring in the context of the invention according to embodiment II represents a 6-membered aromatic heterocyclic ring in the case of R20, a 5-membered aromatic heterocyclic ring having 1 heteroatom in the case of R21/R2, and a 5- to 6-membered aromatic or saturated heterocyclic ring in the case of A2, and a saturated or partly unsaturated 3- to 7-membered heterocyclic ring in the case of the group NR23R24. Examples which may be mentioned are: pyridazinyl, quinolyl, isoquinolyl, pyrazinyl, pyridyl, pyrimidyl, thienyl, furyl, morpholinyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrahydropyranyl or tetrahydrofuranyl.
Preferred compounds of the general formula (II-I) according to the invention are those in which
R20 represents a radical of the formula 
which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl and/or by a group of the formula
xe2x80x83xe2x80x94NR23R24,
xe2x80x83wherein
R23 and R24 are identical or different and denote hydrogen or straight-chain or branched acyl having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, amino or by straight-chain or branched alkoxy having up to 3 carbon atoms, or
R23 and R24, together with the nitrogen atom, form a morpholine ring or a radical of the formula 
and/or are substituted by straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino,fluor, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms or by a radical of the formula xe2x80x94OR26, wherein
R26 denotes straight-chain or branched acyl having up to 4 carbon atoms,
and/or are optionally substituted by a radical of the formula 
xe2x80x83wherein
b2 and b2xe2x80x2 are identical or different and denote the number 0, 1, 2 or 3,
a2 denotes the number 1, 2 or 3,
R30 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R21 and R22, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
A2 represents phenyl, or represents tetrahydropyranyl, furyl, tetrahydrofuranyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
and/or are substituted by a group of the formula xe2x80x94(CO)2xe2x80x94NR34R35 wherein
d2 denotes the number 0 or 1,
R34 and R35 are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms,
their isomeric forms and salts and their N-oxides.
Particularly preferred compounds of the general formula (II-I) according to the invention are those in which
R20 represents a radical of the formula 
wherein the ring systems are optionally substituted up to 3 times in an identical or different manner by formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, methylamino, amino, fluorine, chlorine, bromine, cyano, azido or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms,
and/or are optionally substituted by a radical of the formula 
R21 and R22, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,
A2 represents phenyl, tetrahydropyranyl, tetrahydrofuranyl, furyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or. branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or represents straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,
and/or are substituted by a group of the formula xe2x80x94(CO)d2xe2x80x94NR34R35, wherein
d2 denotes the number 0 or 1,
R34 and R35 are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms,
their isomeric forms, salts and N-oxides.
Especially preferred compounds of the general formula (II-I) according to the invention are those in which
R20 represents a radical of the formula 
wherein the abovementioned heterocyclic ring systems are optionally substituted up to 3 times in an identical or different manner by methyl, fluorine, formyl, amino, cyano, methoxy, methoxycarbonyl, methylamino, chlorine or by a radical of the formula 
R21 and R22, including the double bond, together form a phenyl ring and
A2 represents phenyl, which is optionally substituted by fluorine or cyano, and their isomeric forms, salts and N-oxides.
The invention furthermore relates to processes for the preparation of compounds of the general formula (II-I), characterized in that
[A2] compounds of the general formula (II-II) 
in which
R20, R21 and R22 have the abovementioned meaning,
are reacted with compounds of the general formula (II-III)
D2xe2x80x94CH2xe2x80x94A2xe2x80x83xe2x80x83(II-III)
in which
A2 has the abovementioned meaning, and
D2 represents triflate or halogen, preferably bromine,
in inert solvents, if appropriate in the presence of a base, or
[B2] compounds of the general formula (II-IV) 
in which
A2, R21 and R22 have the abovementioned meaning and
L2 represents a radical of the formula xe2x80x94SnR36 R37R3, ZnR39, iodine or triflate, wherein
R36, R37 and R38 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and
R39 denotes halogen,
are reacted with compounds of the general formula (II-V)
R20xe2x80x94T2xe2x80x83xe2x80x83(II-V)
in which
R20 has the abovementioned meaning and
in the case where L2=SnR36R37R38 or ZnR39,
T2 represents triflate or represents halogen, preferably bromine, and
in the case where L2=iodine or triflate,
T2 represents a radical of the formula SnR36R37R38, ZnR39 or BR40R41, wherein
R36xe2x80x2, R37xe2x80x2, R38xe2x80x2 and R39xe2x80x2 have the abovementioned meaning of R36, R37, R38 and R39 and are identical to or different from these and
R40 and R41 are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,
in a palladium-catalysed reaction in inert solvents,
and, in the case of the radicals xe2x80x94S(O)c2NR31R32 and xe2x80x94S(O)cc2xe2x80x2NR31xe2x80x2R32xe2x80x2, starting from the unsubstituted compounds of the general formula (II-I), these are first reacted with thionyl chloride and finally the amine component is employed,
and, if appropriate, the substituents listed under R20, R21, R22 and/or A2 are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.
The processes according to the invention for the preparation of the compounds according to embodiment II can be illustrated by way of example by the following equations: 
Suitable solvents here for the individual steps of process [A2] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.
Bases which can be employed for the process according to the invention according to embodiment II are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trialkyl-(C1-C6)amines), such as triethylamine, or heterocyclic compounds, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine and sodium hydride are preferred.
The base is employed in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (II-II).
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure. Suitable solvents here for process [B2] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.
Suitable palladium compounds in the context of the present invention are in general PdCl2((C6H5)3)2, palladium bis-dibenzylideneacetone (Pd(dba)2), [1,1xe2x80x2-bis-(diphenyl-phosphino)ferrocene]-palladium(II) chloride (Pd(dppf)Cl2) or Pd(P(C6H5)3)4. Pd(P(C6H5)3)4 is preferred.
The compounds of the general formulae (II-III) and (II-V) are known or can be prepared by customary methods.
The compounds of the general formula (II-II) are known in some cases and can be prepared by a process in which compounds of the general formula (II-VI) 
in which
R21 and R22 have the abovementioned meaning and
L2xe2x80x2 has the abovementioned meaning of L2 and is identical to or different from this, are reacted with compounds of the general formula (II-V) analogously to the abovementioned process [B2].
The compounds of the general formula (II-IV) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by a process in which compounds of the general formula (II-IVa) 
in which
R21, R22 and A2 have the abovementioned meaning, and
L2xe2x88x92 represents triflate or halogen, preferably iodine,
are reacted with compounds of the general formula (II-VII)
(SnR36R37R38)2xe2x80x83xe2x80x83(II-VII)
in which
R36, R37 and R38 have the abovementioned meaning,
under palladium catalysis, as described above.
The compounds of the general formula (II-VII) are known or can be prepared by customary methods.
The compounds of the general formula (II-IVa) are new in most cases and can be prepared by a process in which compounds of the general formula (II-VIII) 
in which
R21 and R22 have the abovementioned meaning,
are reacted with the abovementioned compounds of the general formula (II-V)
R20xe2x80x94T2xe2x80x83xe2x80x83(II-V)
wherein R20 and T2 have the abovementioned meaning,
in one of the abovementioned solvents, preferably tetrahydrofuran, and in the presence of sodium hydride in a temperature range from 0xc2x0 C. to 40xc2x0 C., preferably at room temperature and under an inert gas atmosphere.
The compounds of the general formula (II-VIII) are known in most cases or can be prepared by customary methods.
The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydrido-boranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.
The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.
The reduction in general proceeds in a temperature range from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C., in the case of DIBAH, 0xc2x0 C., room temperature in the case of NaBH4, particularly preferably at xe2x88x9278xc2x0 C, in each case depending on the choice of reducing agent and solvents.
The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.
In the case where the radicals of the formulae xe2x80x94S(O)c2NR31R32xe2x80x2and xe2x80x94S(O)c2xe2x80x2NR31xe2x80x2R32xe2x80x2 are substituted, the corresponding unsubstituted compounds are first reacted with thionyl chloride and reacted with the amines in the presence of the abovementioned ethers, preferably dioxane, in a second step and in the case where c2=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in general in a temperature range from 0xc2x0 C. to 70xc2x0 C. under normal pressure.
The protective group is in general split off in one of the abovementioned alcohols and/or THF or acetone, preferably methanol/THF, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0xc2x0 C. to 70xc2x0 C., preferably at room temperature under normal pressure.
The invention moreover relates to the combination of the compounds of the general formula (II-I) according to the invention with organic nitrates and NO donors.
Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the liberation of NO or NO species. Sodium nitroprusside (SNP), nitroglycerol, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.
The invention also relates to the combination with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular, inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pages 150-155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect increased by these inhibitors.
The compounds of the general formula (II-I) according to the invention show an unforeseeable, valuable pharmacological action spectrum.
The compounds of the general formula (II-I).according to the invention lead to a vessel relaxation/inhibition of platelet aggregation and to a lowering of blood pressure, as well as to an increase in coronary blood flow. These actions are mediated via direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. Furthermore, the compounds according to the invention intensify the action of substances which increase the cGMP level, such as, for example, EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
They can therefore be employed in medicaments for treatment of cardiovascular diseases, such as, for example, for treatment of high blood pressure and cardiac insufficiency, stable and unstable angina. pectoris and peripheral and cardiac vascular diseases and of arrhythmias, for treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transitory and ischaemic attacks and peripheral circulatory disturbances, for preventing restenoses, such as after thrombolysis treatment, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass, and for treatment of arteriosclerosis and diseases of the urogenital system, such as, for example, prostate hypertrophy, erectile dysfunction and incontinence.
The following investigations were carried out to determine the cardiovascular actions: the influence on guanylate cyclase-dependent cGMP formation with and without an NO donor was tested in investigations in vitro on cells of vascular origin. The anti-aggregatory properties were demonstrated on human platelets stimulated with collagen.
The vessel-relaxing action was determined on rabbit aortic rings precontracted with phenylephrine. The antihypertensive action was investigated on anaesthetized rats.
Stimulation of Soluble Guanylate Cyclase in Primary Endothelial Cells
Primary endothelial cells were isolated from pig aortas by treatment with collagenase solution. The cells were then cultured in a culture medium until confluence was reached. For the investigations, the cells were subjected to passaging, sown in cell culture plates and subcultured until confluence was reached. To stimulate the endothelial guanylate cyclase, the culture medium was sucked off and the cells were washed once with Ringer""s solution and incubated in stimulation buffer with or without an NO donor (sodium nitroprusside, SNP, 1 xcexcM). Thereafter, the test substances (final concentration 1 xcexcM) were pipetted onto the cells. At the end of the 10-minute incubation period, the buffered solution was sucked off and the cells were lysed at xe2x88x9220xc2x0 C. for 16 hours. The intracellular cGMP was then determined radioimmunologically.
Vessel-relaxing Action in Vitro
Rings 1.5 mm wide of an aorta isolated from a rabbit are introduced individually, under pretension, in 5 ml organ baths with Krebs-Henseleit solution warmed to 37xc2x0 C. and gassed with carbogen. The contraction force is amplified and digitalized and recorded in parallel on a line recorder. To generate a contraction, phenylephrine is added cumulatively to the bath in an increasing concentration.
After several control cycles, the substance to be investigated is investigated in each further pass in each case in an increasing dosage, and a comparison is made with the level of the contraction achieved in the last preliminary pass. The concentration necessary to reduce the level of the control value by 50% (IC50) is calculated from this. The standard application volume is 5 xcexcl.
Blood Pressure Measurements on Anaesthetized Rats
Male Wistar Rats with a body weight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is inserted into the femoral artery for blood pressure measurement. The substances to be tested are administered orally by means of a stomach tube in various doses as a suspension in tylose solution.
Inhibition of Platelet Aggregation in Vitro
To determine the platelet aggregation-inhibiting action, blood from healthy subjects of both sexes was used. One part of 3.8% strength aqueous sodium citrate solution was admixed to 9 parts of blood as an anticoagulant. Platelet-richer citrate plasma (PRP) is obtained from this blood by means of centrifugation.
For these investigations, 445 xcexcl of PRP and 5 xcexcl of the active compound solution were preincubated in a water-bath at 37xc2x0 C. The platelet aggregation was then determined by the turbidometric method in an aggregometer at 37xc2x0 C. For this, 50 xcexcl of collagen, an aggregation-inducing agent, were added to the preincubated sample and the change in optical density was recorded. For the quantitative evaluation, the maximum aggregation response was determined and the percentage inhibition compared with the control was calculated therefrom.
The compounds described in the present invention in embodiment II are also active compounds for combating diseases in the central nervous system which are characterized by impairments of the NO/cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory performance and for treatment of Alzheimer""s disease. They are also suitable for treatment of diseases of the central nervous system such as states of anxiety, stress and depression, sexual dysfunctions of central nervous origin and sleep disturbances, and for regulating pathological disturbances in the intake of food and addictive substances.
These active compounds are furthermore also suitable for regulation of cerebral circulation and are therefore effective agents for combating migraine.
They are also suitable for prophylaxis and combating the consequences of cerebral infarction events (apoplexia cerebri), such as apoplexy, cerebral ischaemias and cranio-cerebral trauma. The compounds according to the invention can also be employed for combating states of pain.
The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.
If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.
The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.
In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.
III
The present invention relates to new 3-heterocyclyl-substituted pyrazole derivatives, in the embodiment designated III (roman three) of the general formula (III-I) 
in which
R42 represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula xe2x80x94OR45, wherein
R45 denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula xe2x80x94SiR46R47R48, wherein
R46, R47 and R48 are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms,
and/or can be substituted by a radical of the formula 
wherein
a3, b3 and b3xe2x80x2 denote the number 0, 1, 2 or 3,
R49 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
c3 denotes the number 1 or 2 and
R50 and R51 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or
denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or
R50 and R51, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical xe2x80x94NR52, wherein
R52 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula 
or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen,
R43 and R44, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,
and/or are optionally substituted by a group of the formula xe2x80x94S(O)c3xe2x80x2NR50xe2x80x2R51xe2x80x2, wherein c3xe2x80x2, R50xe2x80x2 and R51xe2x80x2 have the abovementioned meaning of c3, R50 and R51 and are identical to or different from these,
A3 represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O, or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,
and/or is substituted by a group of the formula xe2x80x94(CO)d3xe2x80x94NR53R54, wherein
d3 denotes the number 0 or 1,
R53 and R54 are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms,
and their isomeric forms and salts.
The compounds of the general formula (III-I) according to the invention can also be present in the form of their salts with organic or inorganic bases or acids.
In the context of embodiment III of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
The compounds according to the invention can exist in stereoisomeric forms which either behave as mirror images (enantiomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or diastereomers or their particular mixtures. The racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.
Heterocyclic ring in the context of embodiment III of the invention in general, depending on the abovementioned substituents, represents a saturated or aromatic 5- or 6-membered heterocyclic ring, which can contain 1, 2 or 3 heteroatoms from the series consisting of S, N and/or O and, in the case of a nitrogen atom, can also be bonded via this. Examples which may be mentioned are: oxadiazolyl, thiadiazolyl, pyrazolyl, pyrimid pyridyl, thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidyl. Oxazolyl, thiazolyl, pyrazolyl, pyrimidyl, pyridyl or tetrahydropyranyl are preferred.
Preferred compounds of the general formula (III-I) according to the invention are those in which
R42 represents imidazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyranyl or morpholinyl, which are optionally substituted up to twice in an identical or different manner by formyl, trifluoromethyl, phenyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms, or by a radical of the formula xe2x80x94OR45, wherein
R45 denotes straight-chain or branched acyl having up to 4 carbon atoms or a group of the formula xe2x80x94SiR46R47R48, wherein
R46, R47 and R48 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms,
and/or are substituted by a radical of the formula 
xe2x80x83wherein
a3 denotes the number 0, 1, 2 or 3,
R49 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R43 and R44, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
A3 represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, phenyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl,. which are optionally substituted up to twice in an identical or different manner by. hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
and/or are substituted by a group of the formula xe2x80x94(CO)d3xe2x80x94NR53R54, wherein
d3 denotes the number 0 or 1,
R53 and R54 are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms,
and their isomeric forms and salts.
Particularly preferred compounds of the general formula (III-I) according to the invention are those in which
R42 represents imidazolyl, oxazolyl, oxadiazolyl or thiazolyl, which are optionally substituted up to twice in an identical or different manner by formyl, trifluoromethyl, phenyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, fluorine, chlorine, trifluoromethyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms or by the radical of the formula xe2x80x94Oxe2x80x94COxe2x80x94CH3,
and/or are substituted by a radical of the formula 
xe2x80x83wherein
a3 denotes the number 0, 1 or 2,
R49 denotes hydrogen or methyl,
R43 and R44, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,
A3 represents tetrahydropyranyl, phenyl, thienyl, pyrimidyl or pyridyl, which are optior substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,
and/or are substituted by a group of the formula xe2x80x94(CO)d3xe2x80x94NR53R54, wherein
d3 denotes the number 0 or 1,
R53 and R54 are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms,
and their isomeric forms and salts.
Especially preferred compounds of the general formula (III-I) according to the invention are those in which
R42 represents imidazolyl, oxazolyl, thiazolyl or oxadiazolyl, which are optionally substituted up to twice in an identical or different manner by ethoxycarbonyl, phenyl or by methyl or ethyl, wherein the alkyl radicals in their turn can be substituted by hydroxyl, chlorine, ethoxycarbonyl, oxycarbonylmethyl or methoxy,
R43 and R44 together, in changing the double bond, represent phenyl, which is optionally substituted by nitro,
A3 represents phenyl or phenyl which is substituted by fluorine, or pyrimidyl and their isomers and salts.
The invention furthermore relates to processes for the preparation of the compounds of the general formula (III-I) according to the invention, characterized in that
[A3] compounds of the general formula (III-I) 
in which
R42, R43 and R44 have the abovementioned meaning,
are reacted with compounds of the general formula (III-III)
D3xe2x80x94CH2xe2x80x94A3xe2x80x83xe2x80x83(III-III)
in which
A3 has the abovementioned meaning and
D3 represents triflate or halogen, preferably bromine,
in inert solvents, if appropriate in the presence of a base, or
[B3] compounds of the general formula (III-IV) 
in which
A3, R43 and R44 have the abovementioned meaning and
L3 represents a radical of the formula xe2x80x94SnR55R56R57, ZnR58, iodine, bromine or triflate, wherein
R55, R56 and R57 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and
R58 denotes halogen,
are reacted with compounds of the general formula (III-V)
R42xe2x80x94T3xe2x80x83xe2x80x83(III-V),
in which
R42 has the abovementioned meaning and
in the case where L3=SnR55R56R57 or ZnR58,
T3 represents triflate or represents halogen, preferably bromine, and
in the case where L3=iodine, bromine or triflate,
T3 represents a radical of the formula SnR55R56R57, ZnR58 or BR59R60, wherein
R55xe2x80x2, R56xe2x80x2, R57xe2x80x2 and R58xe2x80x2 have the abovementioned meaning of R55, R56, R57 and R58 and are identical to or different from these, and
R59 and R60 are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,
in a palladium-catalysed reaction in inert solvents, or
[C3] in the case where 
in which
R61 represents straight-chain or branched alkyl having up to 4 carbon atoms, compounds of the general formula (III-VI) 
in which
A3, R43 and R4 have the abovementioned meaning,
are reacted with diazo compounds of the general formula (III-VII) 
in which
R62 represents straight-chain or branched alkyl having up to 4 carbon atoms, in the presence of copper salts or rhodium salts to give compounds of the general formula (III-Ia) 
in which
A3, R43, R44 and R62 have the abovementioned meaning,
[D3] in the case where R42=
compounds of the general formula (III-VIII) 
in which
A3, R43 and R44 have the abovementioned meaning,
are either converted directly by reaction with the compound of the formula (III-IX) 
in the system NaOCOxe2x80x94CH3/N-methylpyrrolidine
into the compounds of the general formula (III-Ib) 
in which
R43, R44 and A3 have the abovementioned meaning,
and the acetyl group is then split off by the action of potassium hydroxide in methanol, or
by reaction of the compounds of the general formula (III-VIII) with the compound of the formula (III-IX), the compounds of the general formula (III-X) 
in which
R43, R44 and A3 have the abovementioned meaning,
are first prepared,
and the hydroxymethyl compounds are prepared in a further step by the action of potassium hydroxide,
and, if appropriate, are converted into the corresponding alkoxy compounds by an alkylation by customary methods, or
[E3] compounds of the general formula (III-XI) 
in which
A3, R43 and R44 have the abovementioned meaning,
by reaction with the compound of the formula (III-XII) 
the compounds of the general formula (III-XIII) 
in which
A3, R43 and R44 have the abovementioned meaning,
are prepared,
and are then reacted in the context of a retro-Diels-Alder reaction (cf. J. Org. Chem, 988, 58, 3387-90), or
[F3] compounds of the general formula (III-XIV) 
in which
A3, R43 and R44 have the abovementioned meaning,
are reacted with compounds of the general formula (III-XV)
Brxe2x80x94CH2xe2x80x94COxe2x80x94R63xe2x80x83xe2x80x83(III-XV),
in which
R63 denotes straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 4 carbon atoms,
in inert solvents to give the compounds of the general formula (III-Ic) 
in which
A3, R43, R44 and R63 have the abovementioned meaning (cf. Oxazoles, J. Wiley/New York, 1986, page 11/12),
and, in the case of the esters (R63=CO2xe2x80x94(C1-C4-alkyl), a reduction is carried out by customary methods to give the corresponding hydroxymethyl compounds, or
[G3] in the case where R42=
carboxylic acids of the general formula (III-XVI) 
in which
A3, R43 and R44 have the abovementioned meaning,
are first converted with hydrazine hydrate into the compounds of the general formula (III-XVII) 
in which
A3, R43 and R44 have the abovementioned meaning,
in a further step, with the compound of the formula (III-XVIII)
Clxe2x80x94COxe2x80x94CH2xe2x80x94Clxe2x80x83xe2x80x83(III-XVIII)
the compounds of the general formula (III-XIX) 
in which
A3, R43 and R44 have the abovementioned meaning,
are prepared
then under the action of phosphorus oxytrichloride, cyclization is carried out to give the compounds of the general formula (III-Id) 
in which
A3, R43 and R44 have the abovementioned meaning,
and, as already described above, the xe2x80x94CH2xe2x80x94OH-substituted compounds are prepared via the stage of the corresponding xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94CH3-substituted compounds (cf. Arzn. Forsch. 45 (1995) 10, 1074-1078), or
[H3] in the case where R42 represents a radical of the formula 
wherein
R64 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms and
R65 has the scope of meaning of the secondary substituents listed above under the heterocyclic radical R42,
compounds of the general formula (III-XX) 
in which
A3, R43, R44, R64 and R65 have the abovementioned meaning,
are reacted in the system PPh3/I2 in the presence of a base, preferably with triethylamine, or
[I3] in the case where R42 represents a radical of the formula 
wherein a3 has the abovementioned meaning,
compounds of the general formula (III-XXI) 
in which
A3, R43 and R44 have the abovementioned meaning and
R66 has the abovementioned meaning of R64 and is identical to or different from this,
either are first converted by reduction by customary methods into the compounds of the general formula (III-XXII) 
in which
A3, R43 and R44 have the abovementioned meaning,
and the compounds of the general formula (III-XXIII) 
in which
A3, R43 and R44 have the abovementioned meaning,
are then prepared by oxidation, or
the compounds of the general formula (III-XXI) are converted directly by reduction into the compounds of the general formula (III-XXIII),
and, finally, these are reacted with 1,2- or 1,3-dihydroxy compounds by conventional methods, or
[J3] in the case where R42 represents the radical of the formula 
wherein
R67 has the abovementioned meaning of R65 and is identical to or different from this,
either compounds of the general formula (III-XXIV) 
in which
R43 and R44 have the abovementioned meaning and
Q represents hydrogen or represents the xe2x80x94CH2xe2x80x94A3 radical and
R68 represents halogen or straight-chain or branched alkoxy having up to 4 carbon atoms, preferably chlorine, methoxy or ethoxy,
are reacted with compounds of the general formula (III-XXV) 
in which
R67 has the abovementioned meaning,
if appropriate in the presence of a base, and, in the case where Q=H, the products are then reacted with compounds of the general formula A3xe2x80x94CH2xe2x80x94Br (III-XXVI), in which A has the abovementioned meaning, or
compounds of the general formula (III-XXVII) 
in which
A3, R43 and R44 have the abovementioned meaning
are reacted with compounds of the general formula (III-XXVIII)
R67xe2x80x94COxe2x80x94R68xe2x80x83xe2x80x83(III-XXVIII)
in which
R67xe2x80x2 has the abovementioned meaning of R67 and is identical to or different from this and
R68xe2x80x2 has the abovementioned meaning of R68 and is identical to or different from this, if appropriate in the presence of a base,
and, in the case of the radicals xe2x80x94S(O)c3NR50R51 and xe2x80x94S(O)c3xe2x80x2NR50xe2x80x2R51xe2x80x2 starting from the unsubstituted compounds of the general formula (III-I), a reaction first with thionyl chloride and finally with the amine component is carried out,
and, if appropriate, the substituents listed under R42, R43, R44 and/or A3 are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.
The processes according to the invention described above can be explained by way of example by the following equations: 
Suitable solvents here for the individual steps of process [A3] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.
Bases which can be employed for the process according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trialkyl-(C1-C6)amines), such as triethylamine, or heterocyclic compounds, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, N-methylpyrrolidone methylpiperidine or morpholine. It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine, sodium hydride and N-methylpyrrolidone are preferred.
The base is employed in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (III-II).
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.
Suitable solvents here for process [B3] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.
Suitable palladium compounds in the context of the present invention are in general PdCl2(P(C6H5)3)2, palladium bis-dibenzylideneacetone (Pd(dba)2), [1,1xe2x80x2-bis(diphenyl-phosphino)ferrocene]palladium(II) chloride (Pd(dppf)Cl2) or Pd(P(C6H5)3)4xe2x80x2 Pd(P(C6H5)3)4 is preferred.
Suitable solvents for process [C3] are some of the abovementioned solvents, benzene being particularly preferred.
Suitable metal salts in the context of the invention are copper salts or rhodium(II) salts, such as, for example, CuOTf, Cu(acac)2 and Rh(OAc)2. Copper acetylacetonate is preferred.
The salts are employed in catalytic amounts.
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.
Process [D3] according to the invention is carried out with one of the abovementioned cyclic amine bases, preferably with N-methylpyrrolidone, in a temperature range from 100xc2x0 C. to 200xc2x0 C., preferably at 150xc2x0 C.
Process [E3] according to the invention is carried out in a temperature range from 150xc2x0 C. to 210xc2x0 C., preferably at 195xc2x0 C.
Process [F3] according to the invention is in general carried out in one of the abovementioned ethers, preferably in tetrahydrofuran at the reflux temperature.
The reaction of the free methylhydroxy group to give the corresponding methylalkoxy compounds is carried out by customary methods by alkylation with alkyl halides, preferably alkyl iodides, in the presence of one of the abovementioned bases, preferably sodium hydride.
The compounds of the general formulae (III-III), (III-V), (III-VI), (III-VII), (III-VIII), (III-IX), (III-XI), (III-XII), (III-XIV), (III-XVI) and (III-XVIII) are known per se or can be prepared by customary methods.
The compounds of the general formula (III-II) are known in some cases and can be prepared by a process in which compounds of the general formula (III-XXXIX) 
in which
R43 and R44 have the abovementioned meaning and
L3xe2x80x2 has the abovementioned meaning of L3 and is identical to or different from this,
are reacted with compounds of the general formula (III-V) analogously to the abovementioned process [B3].
The compounds of the general formula (III-IV) are known in some cases or, in the case of the stannyls, are new and can be prepared, for example, by a process in which the compounds of the general formula (III-IVa) 
in which
R43, R44 and A3 have the abovementioned meaning, and
L3xe2x80x2 represents triflate or halogen, preferably iodine,
are reacted with compounds of the general formula (III-XXX)
(SnR55R56R57)2xe2x80x83xe2x80x83(III-XXX),
wherein
R55, R56 and R57 have the abovementioned meaning
under palladium catalysis as described above.
The compounds of the general formulae (III-IVa) and (III-XXX) are known or can be prepared by customary methods.
The compounds of the general formulae (III-X), (III-XIII), (III-XVII) and (III-XIX) are new in some cases and can be prepared, for example, as described above.
Process [H3] proceeds by customary methods in the context of the invention, in particular in accordance with the descriptions from the publications P. Wipf, C P. Miller, J. Org. Chem. 1993, 58, 3604, C. S. Moody et al., Synlett 1966, page 825.
The compounds of the general formula (III-XX) are known in some cases or can be prepared from the corresponding amides by reaction with (xcex1-diazo-xcex2-keto esters under rhodium salt catalysis (in this context, cf. C. J. Moody et al., Synlett 1996, 825).
Process [I3] is carried out by the customary methods for the preparation of acetals. The reduction steps are described in detail below.
The compounds of the general formulae (III-XXI), (III-XXII) and (III-XXIII) are known in some cases or are new as a species, and can then be prepared as described above.
Process [I3] is carried out analogously to the publications S. Chim and H. J. Shirie, J. Heterocycl. Chem. 1989, 26, 125 and J. Med. Chem. 1990, 33, 113.
The compounds of the general formulae (II-XXIV) and (III-XXV) are known in some cases or can be prepared by customary methods.
The compounds of the general formula (III-XXVI) are known in some cases or are new, and can then be prepared from the corresponding cyano-substituted compounds and hydroxylamine hydrochloride. If appropriate, a base, preferably sodium methanolate in methanol, can be added for this reaction.
The compounds of the general formula (III-XXVII) are known per se or can be prepared by customary methods.
Processes [H3] to [J3] in general proceed in a temperature range from 0xc2x0 C. up to the particular reflux temperature under normal pressure.
The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydrido-boranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.
The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.
The reduction in general proceeds in a temperature range from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C., in the case of DIBAH, Oxc2x0 C., room temperature in the case of NaBH4, particularly preferably at xe2x88x9278xc2x0 C., in each case depending on the choice of reducing agent and solvents.
The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.
The protective group is in general split off in one of the abovementioned alcohols and/or tetrahydrofuran or acetone, preferably methanol/tetrahydrofuran, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0xc2x0 C. to 70xc2x0 C., preferably at room temperature under normal pressure.
In the case where the radicals of the formulae xe2x80x94S(O)c3NR50R51 and xe2x80x94S(O)c3xe2x80x2NR50xe2x80x2R51xe2x80x2 are present, the corresponding unsubstituted compounds are first reacted with thionyl chloride. The reaction with the amines in one of the abovementioned ethers, preferably dioxane, is carried out in a further step. In the case where c3=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in a temperature range from 0xc2x0 C. to 70xc2x0 C. under normal pressure.
Compounds according to the invention according to embodiment III in which R42 represents an oxazolyl radical of the formula (III-XXVIII) 
wherein Y and Z have the meaning given below can preferably be prepared by the new process described below, which can be used generally for the preparation of oxazolyl compounds of this type.
The invention thus furthermore relates to a process for the preparation of oxazolyl compounds of the general formula (III-XXIX) 
in which
X and Y are identical or different and can represent optionally substituted aliphatic, cycloaliphatic, araliphatic, aromatic and heterocyclic radicals, including saturated, unsaturated or aromatic, heteromono- or heteropolycyclic radicals,
carboxyl, acyl, alkoxy, alkoxycarbonyl or cyano or can represent hydrogen, wherein the aromatic and heterocyclic radicals can be substituted by one or more substituents which are chosen from the group which consists of:
halogen, formyl, acyl, carboxyl, hydroxyl, alkoxy, aroxy, acyloxy, optionally alkyl-substituted amino, acylamino, aminocarbonyl, alkoxycarbonyl, nitro, cyano, phenyl and
alkyl, which can be substituted by one or more substituents which are chosen from the group which consists of:
halogen, hydroxyl, amino, carboxyl, acyl, alkoxy, alkoxycarbonyl
and heterocyclyl and phenyl, which can be substituted by one or more substituents chosen from:
amino, mercaptyl, hydroxyl, formyl, carboxyl, acyl, alkylthio, alkyloxyacyl, alkoxy, alkoxycarbonyl, nitro, cyano, trifluoromethyl, azido, halogen, phenyl and alkyl which is optionally substituted by hydroxyl, carboxyl, acyl, alkoxy or alkoxycarbonyl,
and wherein the aliphatic, cycloaliphatic and araliphatic radicals can be substituted by one or more substituents which are chosen from the group which consists of: fluorine, hydroxyl, alkoxy, aroxy, acyloxy, alkyl-substituted amino, acylamino, aminocarbonyl, alkoxycarbonyl and acyl,
Z is chosen from the group which consists of:
hydroxyl, alkoxy, optionally alkyl- and/or halogen-substituted arylalkoxy, optionally alkyl- and/or halogen-substituted aroxy, aroyloxy, acyloxy, alkylthio, optionally alkyl- and/or halogen-substituted arylthio, diacylimido or a group of the formula (III-XXX) 
in which Y and X have the abovementioned meaning,
characterized in that amides of the formula (III-XXXI) 
in which Y and X have the abovementioned meaning and Hal represents chlorine or bromine, are reacted with compounds of the formula M1+Zxe2x88x92 or M22+(Zxe2x88x92)2, in which M1 is an alkali metal, M2 is an alkaline earth metal and Z is as defined above.
In respect of concrete examples which contain the above definitions of the substituents in their scope, reference is made to the corresponding meanings in the explanations given above on the compounds of embodiment III of the present invention.
In a preferred embodiment of this process, oxazolyl compounds of the present invention in which X in the above general formula (III-XXIX) is 
wherein R43, R44 and A3 are as defined above and Y is alkyl or optionally alkyl- or halogen-substituted phenyl,
are prepared.
Examples which may be mentioned of oxazoles which are obtained by the preparation process are: 2,4-dimethyl-5-methoxymethyl-oxazole, 2-ethyl-5-methoxymethyl-oxazole, 2-isopropyl-4-ethyl-5-ethoxymethyl-oxazole, 2-cyclopropyl-4-hexyl-5-isopropoxymethyl-oxazole, 2-phenyl-4-methyl-5-methoxymethyl-oxazole, 2-(m-trifluoromethyl-phenyl)-4-methyl4-butoxymethyl-oxazole, 4-methyl-5-methoxymethyl-2-(m-trifluorophenyl)-oxazole, 2-phenyl-4-methyl-5-phenoxymethyl-oxazole, 2-(2-chloro-6-fluorophenyl)-4-methyl-5-p-tert-butylphenoxymethyl-oxazole, 2,4-dimethyl-5-acetoxymethyl-oxazole, 2,4-dimethyl-5-(3-heptylcarbonyloxy)methyl-oxazole, 2-phenyl-4-methyl-5-acetoxymethyl-oxazole, 2-(1-benzylindazol-3-yl)-5-hydroxymethyl-4-methyl-oxazole, 5-acetoxymethyl-2-(1-benzylindazol-3-yl)-4-methyl-oxazole, 2-(1-benzylindazol-3-yl)-5-methoxymethyl-4-methyl-oxazole, 2-[1-(2-fluorobenzyl)indazol-3-yl]-5-hydroxymethyl-4-methyl-oxazole, 2-[1-(2-fluorobenzyl)-indazol-3-yl]-5-methoxymethyl-4-methyl-oxazole, 2-[1-(2-fluorobenzyl)indazol-3-yl]-4-methyl-5-(N-phthalimidomethyl)-oxazole, 4-ethyl-2-[1-(2-fluorobenzyl)-indazol-3-yl]-5-hydroxymethyl-oxazole, 2-phenyl-4-ethyl-5-benzoyloxymethyl-oxazole, 2-phenyl-4-methyl-5-methylmercaptomethyl-oxazole, bis[(2-phenyl4-methyl-oxazol-5-yl)methyl]disulphide and 2-phenyl-4-methyl-5-N-phthalimidomethyl-oxazole.
The process according to the invention for the preparation of the oxazole compounds is carried out, for example, by a process in which amides are reacted, according to equation (a), with compounds of the formula M1+Zxe2x88x92 or M22+(Zxe2x88x92)2: 
M1 in the compound M1+Zxe2x88x92 is an alkali metal chosen from, for example, lithium (Li), sodium (Na) or potassium (K), preferably sodium or potassium. Examples which may be mentioned of compounds of the formula M1+Zxe2x88x92 are alcoholates, such as Na methylate, Na butylate or K tert-butylate, phenolates, such as Na phenolate and Na 4-tert-butyl-phenolate, carboxylic acid salts, such as Na acetate or K acetate, Li butyrate, Na benzoate and Na 2,6-difluorobenzoate, phthalimide salts, such as K phthalimides and Na phthalimides, hydroxides, such as KOH, NaOH and LiOH, mercaptides, such as the sodium salts of methylmercaptan or thiophenol, and Na2S2, which leads to the disulphide of the formula 
M2 in the compound M22+(Zxe2x88x92)2 is an alkaline earth metal chosen from, for example, magnesium or calcium.
The reaction according to the invention in accordance with equation (a) is carried out in solvents at temperatures from about 20xc2x0 C. to 200xc2x0 C. Suitable solvents are polar compounds, such as, for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, N-methyl-p-caprolactam and dimethyl sulphoxide, and compounds of the formula Zxe2x80x94H are furthermore also possible as solvents, for example the reaction of the amides with Na methylate can be carried out successfully in methanol. Addition of basic auxiliaries, such as, for example, K2CO3 or Cs2CO3, may be advantageous. The resulting oxazoles are isolated, after removal of insoluble salts by filtration and, if appropriate, removal of solvents by distillation, by extraction of the oxazoles with suitable solvents, such as, for example, hydrocarbons, such as cyclohexane or toluene, or chlorohydrocarbons, such as, for example, methylene chloride or chlorobenzene, or esters, such as ethyl acetate or ethers, from the crude product, to which water has been added to remove water-soluble products. The crude product can be purified by customary processes, such as, for example, distillation or crystallization or by chromatography.
The amides as starting compounds are obtained by known processes, for example starting from compounds of the formula a, b or c. 
a: Hal=Cl or Br; Lv=NH2
b: Hal=Cl or Br; Lv=OH
c: Hal=Cl or Br; Lv=Cl or Br
Starting from amines of the formula a, amines of the formula (III-XXXI) are obtained in a known manner by reaction with corresponding acylating agents, such as, for example, acid halides, esters or acids.
Starting from compounds of the formula b or c, amides are obtained in a known manner by reaction with nitriles in the presence of strong acids.
Amides corresponding to the formula a are accessible, for example, by hydrolysis under acid conditions from amides, which are obtained in a known manner by a Ritter reaction from alkyl halides or allyl alcohols of the formula b and c. Finally, such amines can also be obtained via allylic nucleophilic substitution with, for example, phthalimide salts from the corresponding allyl halides of the formula c via the stage of the corresponding substituted phthalimides and subsequent solvolysis.
Compounds of the formula b are readily accessible according to equation (b) and (c) in two reaction steps from simple starting materials in a known manner: 
Compounds of the formula c are obtained in a known manner, for example by addition, initiated by free radicals, of carbon tetrachloride or tetrabromide onto corresponding olefinic compounds and subsequent elimination of hydrogen halide in accordance with equation (d): 
The invention moreover relates to the combination of the compounds of the general formulae (III-I)/(III-Ia) according to the invention with organic nitrates and NO donors.
Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the liberation of NO or NO species. Sodium nitroprusside (SNP), nitroglycerol, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.
The invention also relates to the combination with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular, inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pages 150-155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect increased by these inhibitors.
The compounds of the general formulae (III-I)/(III-Id) according to the invention show an unforeseeable, valuable pharmacological action spectrum.
The compounds of the general formulae (III-I)/(III-Id) according to the invention lead to a vessel relaxation/inhibition of platelet aggregation and to a lowering of blood pressure, as well as to an increase in coronary blood flow. These actions are mediated via direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. Furthermore, the compounds according to the invention intensify the action of substances which increase the cGMP level, such as, for example, EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
They can therefore be employed in medicaments for treatment of cardiovascular diseases, such as, for example, for treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris and peripheral and cardiac vascular diseases and of arrhythmias, for treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transitory and ischaemic attacks and peripheral circulatory disturbances, for preventing restenoses, such as after thrombolysis treatment, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass, and for treatment of arteriosclerosis and diseases of the urogenital system, such as, for example, prostate hypertrophy, erectile dysfunction and incontinence.
The following investigations were carried out to determine the cardiovascular actions: the influence on guanylate cyclase-dependent cGMP formation with and without an NO donor was tested in investigations in vitro on cells of vascular origin. The anti-aggregatory properties were demonstrated on human platelets stimulated with collagen. The vessel-relaxing action was determined on rabbit aortic rings precontracted with phenylephrine. The antihypertensive action was investigated on anaesthetized rats.
Stimulation of Soluble Guanylate Cyclase in Primary Endothelial Cells
Primary endothelial cells were isolated from pig aortas by treatment with collagenase solution. The cells were then cultured in a culture medium until confluence was reached. For the investigations, the cells were subjected to passaging, sown in cell culture plates and subcultured until confluence was reached. To stimulate the endothelial guanylate cyclase, the culture medium was suctioned off and the cells were washed once with Ringer""s solution and incubated in stimulation buffer with or without NO donor (sodium nitroprusside, SNP, 1 xcexcM). Thereafter, the test substances (final concentration 1 xcexcM) were pipetted onto the cells. At the end of the 10-minute incubation period, the buffer solution was suctioned off and the cells were lysed at xe2x88x9220xc2x0 C. for 16 hours. The intracellular cGMP was then determined radioimmunologically.
Vessel-relaxing Action in Vitro
Rings 1.5 mm wide of an aorta isolated from a rabbit are introduced individually, under pretension, in 5 ml organ baths with Krebs-Henseleit solution warmed to 37xc2x0 C. and gassed with carbogen. The contraction force is amplified and digitalized and recorded in parallel on a line recorder. To generate a contraction, phenylephrine is added cumulatively to the bath in an increasing concentration.
After several control cycles, the substance to be investigated is investigated in each further pass in each case in an increasing dosage, and a comparison is made with the level of the contraction achieved in the last preliminary pass. The concentration necessary to reduce the level of the control value by 50% (IC50) is calculated from this. The standard application volume is 5 xcexcl.
Blood Pressure Measurements on Anaesthetized Rats
Male Wistar rats with a body weight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is inserted into the femoral artery for blood pressure measurement. The substances to be tested are administered orally by means of a stomach tube in various doses as a suspension in tylose solution.
Inhibition of Platelet aggregation in Vitro
To determine the platelet aggregation-inhibiting action, blood from healthy subjects of both sexes was used. One part of 3.8% strength aqueous sodium citrate solution was admixed to 9 parts of blood as an anticoagulant. Platelet-richer citrate plasma (PRP) is obtained from this blood by means of centrifugation.
For the investigations, 445 xcexcl of PRP and 5 xcexcl of the active compound solution were preincubated in a water-bath at 37xc2x0 C. The platelet aggregation was then determined in an aggregometer at 37xc2x0 C. using the turbidometric method. For this, 50 xcexcl of collagen, an aggregation-inducing agent, were added to the preincubated sample and the change in optical density was recorded. For the quantitative evaluation, the maximum aggregation response was determined and the percentage inhibition compared with the control was calculated therefrom.
The compounds of embodiment III which are described in the present invention are also active compounds for combating diseases in the central nervous system which are characterized by impairments of the NO/cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory performance and for treatment of Alzheimer""s disease. They are also suitable for treatment of diseases of the central nervous system such as states of anxiety, stress and depression, sexual dysfunctions of central nervous origin and sleep disturbances, and for regulating pathological disturbances in the intake of food and addictive substances.
These active compounds are furthermore also suitable for regulation of cerebral circulation and are therefore effective agents for combating migraine.
They are also suitable for prophylaxis and combating the consequences of cerebral infarction events (apoplexia cerebri), such as apoplexy, cerebral ischaemias and cranio-cerebral trauma. The compounds according to the invention can also be employed for combating states of pain.
The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.
If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.
The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.
In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.
IV
According to embodiment IV, the present invention relates to 1-benzyl-3-(substituted heteroaryl)-fused pyrazole derivatives of the general formula (IV-I) 
in which
A4 represents phenyl, which is optionally substituted up to 3 times in an identical or different manner by halogen, hydroxyl, cyano, carboxyl, nitro, trifluoromethyl, trifluoromethoxy, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms,
R69 represents a radical of the formula 
xe2x80x83wherein
R72 denotes a radical of the formula xe2x80x94CH(OH)xe2x80x94CH3 or straight-chain or branched alkyl having 2 to 6 carbon atoms, which is substituted once to twice by hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, or
denotes formyl, straight-chain or branched acyl having up to 6 carbon atoms, nitro or straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted by amino, azido or by a radical of the formula xe2x80x94OR73, wherein
R73 denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula xe2x80x94SiR74R75R76, 
xe2x80x83wherein
R74, R75 and R76 are identical or different and denote aryl having 6 to 10 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms,
R78 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms and
R79 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or
R72 denotes a group of the formula 
xe2x80x83wherein
R80 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R81 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms and
a4 denotes the number 1, 2 or 3,
b4 and b4xe2x80x2 are identical or different and denote the number 0, 1, 2 or 3,
c4 denotes the number 1 or 2 and
R82 and R83 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or
denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or
denote cycloalkyl having 3 to 7 carbon atoms, or
R82 and R83, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical xe2x80x94NR84, wherein
R84 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula 
or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, or
R72 denotes a group of the formula xe2x80x94CH2xe2x80x94OR85, wherein
R85 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R70 and R71 together form a radical of the formula 
wherein
R86 denotes hydrogen, halogen, hydroxyl, nitro, amino, trifluoromethyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, or a group of the formula xe2x80x94S(O)c4xe2x80x2NR82xe2x80x2R83xe2x80x2, wherein c4xe2x80x2, R82xe2x80x2 and R83xe2x80x2 have the abovementioned meaning of c4, R82 and R83 and are identical to or different from these,
and their isomeric forms and salts,
with the proviso that R72, in the case of the phenyl ring and in the position directly adjacent to the heteroatom, may represent the group of the formula xe2x80x94CH2xe2x80x94OR85xe2x80x2 only if A4 either represents phenyl, which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or is substituted at least twice by the radicals listed above, or R86 represents nitro, amino, trifluoromethyl or represents the group of the formula xe2x80x94S(O)c4NR82xe2x80x2R83xe2x80x2.
The compounds of the general formula (IV-I) according to the invention can also be present in the form of their salts. Salts with organic or inorganic bases or acids may be mentioned in general here.
Physiologically acceptable salts are preferred in the context of embodiment IV of the present invention. Physiologically acceptable salts can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention if they have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
Preferred compounds of the general formula (IV-I) according to the invention are those in which
A4 represents phenyl, which is optionally substituted up to 3 times in an identical or different manner by fluorine, chlorine, bromine, hydroxyl, cyano, carboxyl, nitro, trifluoromethyl, trifluoromethoxy, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms,
R69 represents a radical of the formula 
xe2x80x83wherein
R72 denotes a radical of the formula xe2x80x94CH(OH)xe2x80x94CH3 or straight-chain or branched alkyl having 2 to 4 carbon atoms, which is substituted once to twice by hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or
denotes formyl, straight-chain or branched acyl having up to 4 carbon atoms, nitro or straight-chain or branched alkyl having up to 4 carbon atoms, which is substituted by amino, azido or by a radical of the formula xe2x80x94OR73, wherein
R73 denotes straight-chain or branched acyl having up to 4 carbon atoms or a group of the formula 
xe2x80x83wherein
R78 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms and
R79 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or
k72 denotes a group of the formula 
xe2x80x83wherein
R80 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R81 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms and
a4 denotes the number 1 or 2, or
R72 denotes a group of the formula xe2x80x94CH2xe2x80x94OR85, wherein
R85 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R70 and R71 together form a radical of the formula 
xe2x80x83wherein
R86 denotes hydrogen, fluorine, chlorine, bromine, hydroxyl, nitro, amino, trifluoromethyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms,
and their isomeric forms and salts,
with the proviso that R72, in the case of the phenyl ring and in the position directly adjacent to the heteroatom, may represent the group of the formula xe2x80x94CH2xe2x80x94OR85 only if A4 either represents phenyl, which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or is substituted at least twice by the radicals listed above, or
R86 represents nitro, amino or trifluoromethyl.
Particularly preferred compounds of the general formula (IV-I) according to the invention are those in which
A4 represents phenyl, which is optionally substituted up to 3 times in an identical or different manner by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,
R69 represents a radical of the formula 
wherein
R72 denotes a radical of the formula xe2x80x94CH(OH)xe2x80x94CH3 or straight-chain or branched alkyl having 2 to 4 carbon atoms, which is substituted once to twice by hydroxyl, methyl or methoxy, or
denotes formyl, straight-chain or branched acyl having up to 3 carbon atoms, nitro or straight-chain or branched alkyl having up to 3 carbon atoms, which is substituted by amino, azido or by a radical of the formula xe2x80x94OR73, wherein
R73 denotes straight-chain or branched acyl having up to 3 carbon atoms or a group of the formula 
xe2x80x83wherein
R78 denotes hydrogen or methyl and
R79 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or
R72 denotes a group of the formula 
xe2x80x83wherein
R80 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R81 denotes hydrogen or methyl and
a4 denotes the number 1 or 2, or
R72 denotes the group of the formula xe2x80x94CH2xe2x80x94OR85, wherein
R85 denotes hydrogen or methyl,
R70 and R71 together form a radical of the formula 
xe2x80x83wherein
R86 denotes hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, amino, hydroxyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms,
and their isomeric forms and salts.
Especially preferred compounds of the general formula (IV-I) according to the invention are those in which
A4 represents phenyl, which is optionally substituted up to twice in an identical or different manner by fluorine, chlorine, methyl, methoxy, cyano, nitro, trifluoromethyl or trifluoromethoxy and
R70 and R71 together, including the double bond, form a phenyl ring, which is optionally substituted by nitro, fluorine, amino or methoxy, with the proviso that R72, in the case of the phenyl ring and in the position directly adjacent to the heteroatom, may represent the group of the formula xe2x80x94CH2OR85 only if A4 either represents phenyl, which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or is substituted at least twice by the radicals listed above, or
R86 represents nitro, amino or trifluoromethyl.
The invention furthermore relates to processes for the preparation of the compounds of the general formula (IV-I) according to the invention, characterized in that
[A4] compounds of the general formula (IV-II)
H2Nxe2x80x94NHxe2x80x94CH2xe2x80x94A4xe2x80x83xe2x80x83(IV-II)
in which
A4 has the abovementioned meaning,
are converted by reaction with compounds of the general formula (IV-III) 
in which
R69 , R70 and R71 have the abovementioned meaning,
into the compounds of the general formula (IVxe2x80x94IV) 
in which
A4, R69, R70 and R71 have the abovementioned meaning,
in inert solvents, if appropriate in the presence of an acid, and the products are finally oxidized and cyclized with lead tetraacetate/BF3xc3x97ether, or
[B4] compounds of the general formula (IV-V) 
in which
R69, R70 and R71 have the abovementioned meaning,
are reacted with compounds of the general formula (IV-VI)
D4xe2x80x94CH2xe2x80x94A4xe2x80x83xe2x80x83(IV-VI)
in which
A4 has the abovementioned meaning and
D4 represents triflate or halogen, preferably bromine,
in inert solvents, if appropriate in the presence of a base, or
[C4] compounds of the general formula (IV-VII) 
in which
A4, R70 and R71 have the abovementioned meaning and
L4 represents a radical of the formula xe2x80x94SnR87R88R89, ZnR90, iodine or triflate wherein
R87, R88 and R89 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and
R90 denotes halogen,
are reacted with compounds of the general formula (IV-VIII)
R69xe2x80x94T4xe2x80x83xe2x80x83(IV-VIII)
in which
R69 has the abovementioned meaning and
in the case where L4=SnR87R88R89 or ZnR90,
T4 represents triflate or represents halogen, preferably bromine, and
in the case where L4=iodine or triflate,
T4 represents a radical of the formula SnR87xe2x80x2R88xe2x80x2R89xe2x80x2, ZnR90xe2x80x2 or BR91R92 wherein
R87xe2x80x2, R88xe2x80x2, R89xe2x80x2 and R90xe2x80x2 have the abovementioned meaning of R87, R88, R89 and R90 and are identical to or different from these and
R91 and R92 are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring
in a palladium-catalysed reaction in inert solvents, or
[D4] in the case where R72 represents an alkyl having 2 to 6 carbon atoms, which is substituted twice by hydroxyl,
compounds of the general formula (IV-Ia) 
in which
A4, R70 and R71 have the abovementioned meaning,
are first converted by a Wittig reaction in the system (C6H5)3P⊕xe2x80x94CH263  into the compounds of the general formula (IV-IX) 
in which
R70, R71 and A4 have the abovementioned meaning,
and finally the hydroxyl functions are introduced with osmium tetroxide,
and, if appropriate, the substituents listed under R69, R70, R71 and/or A4 are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.
The processes according to the invention can be illustrated by way of example by the following equations: 
Suitable solvents for the individual steps of process [A4] are in general inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether, dimethoxyethane or tetrahydrofuran, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, alcohols, such as methanol, ethanol or propanol, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Ethanol and THF are preferred for the first step of process [A4], and methylene chloride is preferred for the cyclization.
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.
Suitable acids are in general carboxylic acids, such as, for example, acetic acid, toluenesulphonic acid, sulphuric acid or hydrogen chloride. Acetic acid is preferred.
Suitable solvents here for the individual steps of process [B4] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.
Bases which can be employed for the process according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trialkyl-(C1-C6)amines), such as triethylamine, or heterocyclic compounds, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine.
It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine and sodium hydride are preferred.
The base is employed in an amount of 1 mol to5 mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (IV-II).
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.
Suitable solvents here for processes [C4] and [D4] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.
The reaction is in general carried out in a temperature range from 0xc2x0 C. to 150xc2x0 C., preferably from +20xc2x0 C. to +110xc2x0 C.
The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.
Suitable palladium compounds in the context of the present invention are in general PdCl2((C6H5)3)2, palladium bis-dibenzylideneacetone (Pd(dba)2), [1,1xe2x80x2-bis-(diphenylphosphino)ferrocene]-palladium(II) chloride (Pd(dppf)Cl2) or Pd(P(C6H5)3)4.
Pd(P(C6H5)3)4 is preferred.
The compounds of the general formulae (IV-II), (IV-III), (IV-VI) and (IV-VIII) are known per se or can be prepared by customary methods.
The compounds of the general formula (IV-IV) are known in some cases or can be prepared as described above.
The compounds of the general formula (IV-V) are known in some cases and can be prepared by a process in which compounds of the general formula (IV-IX) 
in which
R70 and R71 have the abovementioned meaning and
L4 has the abovementioned meaning of L4 and is identical to or different from this,
are reacted with compounds of the general formula (IV-VIII) analogously to the abovementioned process [C4].
The compounds of the general formula (IV-VII) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by a process in which the compounds of the general formula (IV-VIIa) 
in which
R70, R71 and A have the abovementioned meaning, and
L4xe2x80x3 represents triflate or halogen, preferably iodine,
are reacted with compounds of the general formula (IV-X)
(SnR87R88R89)2xe2x80x83xe2x80x83(IV-X)
in which
R87, R88 and R89 have the abovementioned meaning, under palladium catalysis as described above.
The compounds of the general formulae (IV-VIIa), (IV-IX) and (IV-X) are known or can be prepared by customary methods.
The compounds of the general formula (IV-IX) are new and can be prepared as described above.
The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.
The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.
The reduction in general proceeds in a temperature range from xe2x88x9278xc2x0 C. to +50xc2x0 C., preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C., in the case of DIBAH, 0xc2x0 C., room temperature in the case of NaBH4, particularly preferably at xe2x88x9278xc2x0 C., in each case depending on the choice of reducing agent and solvents.
The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.
In the case of the radicals xe2x80x94S(O)c4R81R82 and xe2x80x94S(O)c4xe2x80x2R81xe2x80x2R82xe2x80x2, the corresponding unsubstituted compounds of the general formula (IV-I) are first reacted with thionyl chloride. The reaction with the amines in one of the abovementioned ethers, preferably dioxane, is carried out in a further step. In the case where c4=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in a temperature range from 0xc2x0 C. to 70xc2x0 C. under normal pressure.
The protective group is in general split off in one of the abovementioned alcohols and/or tetrahydrofuran or acetone, preferably methanol/tetrahydrofuran, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0xc2x0 C. to 70xc2x0 C., preferably at room temperature under normal pressure.
The compounds of the general formula (IV-Ic) are new and can be prepared as described under processes [A4] to [C4].
The invention moreover relates to the combination of the compounds of the general formulae (IV-I) and (IV-Ia) according to the invention with organic nitrates and NO donors.
Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the liberation of NO or NO species. Sodium nitroprusside, nitroglycerol, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 are preferred.
The invention also relates to the combination with compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular, inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pages 150-155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect increased by these inhibitors.
The compounds of the general formula (IV-I) and (IV-Ia) according to the invention show an unforeseeable, valuable pharmacological action spectrum.
The compounds of the general formulae (IV-I) and (IV-Ia) according to the invention lead to a vessel relaxation/inhibition of platelet aggregation and to a lowering of blood pressure, as well as to an increase in coronary blood flow. These actions are mediated via direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP. Furthermore, the compounds according to the invention intensify the action of substances which increase the cGMP level, such as, for example, EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
They can therefore be employed in medicaments for treatment of cardiovascular diseases, such as, for example, for treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris and peripheral and cardiac vascular diseases and of arrhythmias, for treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, cerebral stroke, transitory and ischaemic attacks and peripheral circulatory disturbances, for preventing restenoses, such as after thrombolysis treatment, percutaneous transluminal angioplasties (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass, and for treatment of arteriosclerosis and diseases of the urogenital system, such as, for example, prostate hypertrophy, erectile dysfunction and incontinence.
The following investigations were carried out to determine the cardiovascular actions: the influence on guanylate cyclase-dependent cGMP formation with and without an NO donor was tested in investigations in vitro on cells of vascular origin. The anti-aggregatory properties were demonstrated on human platelets stimulated with collagen. The vessel-relaxing action was determined on rabbit aortic rings precontracted with phenylephrine. The antihypertensive action was investigated on anaesthetized rats.
Stimulation of Soluble Guanylate Cyclase in Primary Endothelial Cells
Primary endothelial cells were isolated from pig aortas by treatment with collagenase solution. The cells were then cultured in a culture medium until confluence was reached. For the investigations, the cells were subjected to passaging, sown in cell culture plates and subcultured until confluence was reached. To stimulate the endothelial guanylate cyclase, the culture medium was suctioned off and the cells were washed once with Ringer""s solution and incubated in stimulation buffer with or without an NO donor (sodium nitroprusside, SNP, 1 xcexcM). Thereafter, the test substances (final concentration 1 xcexcM) were pipetted onto the cells. At the end of the 10-minute incubation period, the buffered solution was suctioned off and the cells were lysed at 20xc2x0 C. for 16 hours. The intracellular cGMP was then determined radioimmunologically.
Vessel-Relaxing Action in Vitro
Rings 1.5 mm wide of an aorta isolated from a rabbit are introduced individually, under pretension, in 5 ml organ baths with Krebs-Henseleit solution warmed to 37xc2x0 C. and gassed with carbogen. The contraction force is amplified and digitalized and recorded in parallel on a line recorder. To generate a contraction, phenylephrine is added cumulatively to the bath in an increasing concentration.
After several control cycles, the substance to be investigated is investigated in each further pass in each case in an increasing dosage, and a comparison is made with the level of the contraction achieved in the last preliminary pass. The concentration necessary to reduce the level of the control value by 50% (IC50) is calculated from this.
Blood Pressure Measurements on Anaesthetized Rats
Male Wistar Rats with a bodyweight of 300-350 g are anaesthetized with thiopental (100 mg/kg i.p.). After tracheotomy, a catheter is inserted into the femoral artery for blood pressure measurement. The substances to be tested are administered orally by means of a stomach tube in various doses as a suspension in tylose solution.
The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.
Inhibition of Platelet Aggregation in Vitro
To determine the platelet aggregation-inhibiting action, blood from healthy subjects of both sexes was used. One part of 3.8% strength aqueous sodium citrate solution was admixed to 9 parts of blood as an anticoagulant. Platelet-richer citrate plasma (PRP) is obtained from this blood by means of centrifugation.
For these investigations, 445 xcexcl of PRP and 5 xcexcl of the active compound solution were preincubated in a water-bath at 37xc2x0 C. The platelet aggregation was then determined in an aggregometer at 37xc2x0 C. using the turbidometric method. For this, 50 xcexcl of collagen, an aggregation-inducing agent, were added to the preincubated sample and the change in optical density was recorded. For the quantitative evaluation, the maximum aggregation response was determined and the percentage inhibition compared with the control was calculated therefrom.
The compounds described in the present invention in embodiment IV are also active compounds for combating diseases in the central nervous system which are characterized by impairments of the NO/cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory performance and for treatment of Alzheimer""s disease. They are also suitable for treatment of diseases of the central nervous system such as states of anxiety, stress and depression, and pathological disturbances of central nervous origin in the intake of food and addictive substances.
These active compounds are furthermore also suitable for regulation of cerebral circulation and are therefore effective agents for combating migraine.
They are also suitable for prophylaxis and combating the consequences of cerebral infarction events (apoplexia cerebri), such as apoplexy, cerebral ischaemias and cranio-cerebral trauma. The compounds according to the invention can also be employed for combating states of pain.
The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.
If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.
The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.
In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.
Starting Compounds